The invention relates to substituted 7-azaindoles, process for their preparation, pharmaceutical preparations which comprise these compounds, and the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 4, as active ingredients for the treatment of disorders which can be influenced by inhibition of phosphodiesterase 4 activity in particular in immunocompetent cells (e.g. macrophages and lymphocytes) by the compounds of the invention.
Activation of cell membrane receptors by transmitters leads to activation of the second messenger system. Adenylate cyclase synthesizes the active cyclic AMP (cAMP) and cyclic GMP (cGMP) respectively from AMP and GMP. cAMP and cGMP lead for example in smooth muscle cells to relaxation, and in inflammatory cells to inhibition of mediator release and synthesis. The second messengers cAMP and cGMP are degraded by phosphodiesterases (PDE). To date, 11 families of PDE enzymes (PDE1-11) are known and differ through their substrate specificity (cAMP, cGMP or both) and the dependence on other substrates (e.g. calmodulin). These isoenzymes have different functions in the body and are expressed differently in individual cell types (Beavo, J. A., Conti, M. and Heaslip, R. J., Multiple cyclic nucleotide phosphodiesterases. Mol. Pharmacol. 1994, 46:399–405; Hall, I. P., Isoenzyme selective phosphodiesterase inhibitors: potential clinical uses, Br. J. clin. Pharmacol. 1993, 35:1–7). Inhibition of the various PDE isoenzyme types results in accumulation of cAMP or cGMP in cells, which can be utilized therapeutically (Torphy, T. J., Livi, G. P., Christensen, S. B. Novel Phosphodiesterase Inhibitors for the Therapy of Asthma, Drug News and Perspectives 1993, 6:203–214).
The predominant PDE-isoenzyme in cells important for allergic inflammations (lymphocytes, mast cells, eosinophilic granulocytes, macrophages) is that of type 4 (Torphy, J. T. and Undem, B. J., Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Thorax 1991, 46:512–523). Inhibition of PDE 4 by suitable inhibitors is therefore regarded as an important approach to the therapy of a large number of allergically induced disorders (Schudt, Ch., Dent, G., Rabe, K, Phosphodiesterase Inhibitors, Academic Press London 1996).
An important property of phosphodiesterase 4 inhibitors is inhibition of the release of tumor necrosis factor α (TNFα) from inflammatory cells. TNFα is an important proinflammatory cytokine which influences a large number of biological processes. TNFα is released for example from activated macrophages, activated T lymphocytes, mast cells, basophils, fibroblasts, endothelial cells and astrocytes in the brain. It has itself an activating effect on neutrophils, eosinophils, fibroblasts and endothelial cells, whereby various tissue-damaging mediators are released. The effect of TNFα in monocytes, macrophages and T lymphocytes is increased production of further proinflammatory cytokines such as GM-CSF (granulocyte-macrophage colony-stimulating factor) or interleukin-8. Owing to its proinflammatory and catabolic effect, TNFα plays a central role in a large number of disorders such as inflammations of the respiratory tract, inflammations of the joints, endotoxic shock, tissue rejections, AIDS and many other immunological disorders. Thus, phosphodiesterase 4 inhibitors are likewise suitable for the therapy of such disorders associated with TNFα.
Chronic obstructive pulmonary diseases (COPD) are widespread in the population and also have great economic importance. Thus, COPD disorders are the cause of about 10–15% of all illness costs in the developed countries, and about 25% of all deaths in the USA are attributable to this cause (Norman, P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431–437, 1998). The WHO estimates that COPD will become the third-commonest cause of death in the next 20 years.
The pathological condition of chronic obstructive pulmonary diseases (COPD) encompasses various pathological conditions of chronic bronchitis with the symptoms of coughing and expectoration, and progressive and irreversible deterioration in lung function (expiration is particularly affected). The course of the disease is episodic and often complicated by bacterial infections (Rennard, S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S–241S, 1998). There is a steady decline in lung function during the disorder, the lung becomes increasingly emphysematous, and the patients' breathing difficulty becomes obvious. This disorder markedly impairs the patients' quality of life (shortness of breath, low exercise tolerance) and significantly shortens their life expectancy. Besides environmental factors, the main risk factor is smoking (Kummer, F.: Asthma and COPD. Atemw.-Lungenkrkh. 20 (5), 299–302, 1994; Rennard, S. I.: COPD: Overview of definitions, Epidemiology, and factors influencing its development. Chest, 113 (4) Suppl., 235S–241S, 1998) and thus men are affected distinctly more frequently than are women. However, this picture will change in the future due to the alteration in lifestyles and the increase in the number of female smokers.
Current therapy claims only to alleviate the symptoms without affecting the causes of the progression of the disorder. The use of long-acting beta2 agonists (e.g. salmeterol), possibly in combination with muscarinergic antagonists (e.g. ipratropium), improves lung function through bronchodilatation and is routinely employed (Norman, P.: COPD: New developments and therapeutic opportunities, Drug News Perspect. 11 (7), 431–437, 1998). Bacterial infections play a large part in the episodes of COPD and need antibiotic treatment (Wilson, R.: The role of infection in COPD, Chest, 113 (4) Suppl., 242S–248S, 1998; Grossman, R. F.: The value of antibiotics and the outcomes of antibiotic therapy in exacerbations of COPD. Chest, 113 (4) Suppl., 249S–255S, 1998). Therapy of this disorder is currently unsatisfactory, especially in relation to the continuous decline in lung function. New therapeutic approaches acting on mediators of inflammation, proteases or adhesion molecules might be very promising (Barnes, P. J.: Chronic obstructive disease: new opportunities for drug development, TiPS 10 (19), 415–423, 1998).
Irrespective of the bacterial infections complicating the disorder, a chronic inflammation is found in the bronchi and is dominated by neutrophilic granulocytes. The mediators and enzymes released by neutrophilic granulocytes are thought inter alia to be responsible for the observed structural changes in the respiratory tract (emphysema). Inhibition of the activity of neutrophilic granulocytes is thus a rational approach to the prevention or slowing down of the progression of COPD (deterioration in parameters of lung function). An important stimulus for the activation of granulocytes is the proinflammatory cytokine TNFα (tumor necrosis factor). Thus, it is known that TNFα stimulates the formation of oxygen free radicals by neutrophilic granulocytes (Jersmann, H. P. A.; Rathjen, D. A. and Ferrante, A.: Enhancement of LPS-induced neutrophil oxygen radical production by TNFα, Infection and Immunity, 4, 1744–1747, 1998). PDE4 inhibitors are able to inhibit very effectively the release of TNFα from a large number of cells and thus suppress the activity of neutrophilic granulocytes. The nonspecific PDE inhibitor pentoxifylline is able to inhibit both the formation of oxygen free radicals and the phagocytic ability of neutrophilic granulocytes (Wenisch, C.; Zedtwitz-Liebenstein, K.; Parschalk, B. and Graninger, W.: Effect of pentoxifylline in vitro on neutrophil reactive oxygen production and phagocytic ability assessed by flow cytometry, Clin. Drug Invest., 13(2):99–104, 1997).
Various PDE 4 inhibitors have already been disclosed. These are primarily xanthine derivatives, rolipram analogs or nitraquazone derivatives (review in: Karlsson, J. A., Aldos, D., Phosphodiesterase 4 inhibitors for the treatment of asthma, Exp. Opin. Ther. Patents 1997, 7: 989–1003). It has not been possible to date for any of these compounds to be used clinically. It was unavoidably found that the known PDE4 inhibitors also have various side effects, such as nausea and emesis, which it has not to date been possible to suppress adequately. It is therefore necessary to discover novel PDE4 inhibitors with improved therapeutic index.
Indol-3-ylglyoxylamides and processes for preparing them have already been described several times. In all cases, indoles unsubstituted in position 3, which are synthesized by substitution in position 1 of a commercially available indole, were converted by reaction with oxalyl halides into indol-3-ylglyoxylyl halides which subsequently afford, by reaction with ammonia or with primary or secondary amines, the corresponding indol-3-ylglyoxylamides. (Scheme 1)

Thus, U.S. Pat. Nos. 2,825,734 and 3,188,313 describe various indol-3-ylglyoxylamides which are prepared by the manner depicted in Scheme 1. These compounds were used as intermediates for preparing indole derivatives produced by reductions. U.S. Pat. No. 3,642,803 also describes indol-3-ylglyoxylamides.
The preparation of 5-methoxyindol-3-ylglyoxylamides is described in Farmaco 22 (1967), 229–244. Again there is reaction of the indole derivative used with oxalyl chloride, and the resulting indol-3-ylglyoxylyl chloride is reacted with an amine.
In addition, U.S. Pat. No. 6,008,231 describes indol-3-ylglyoxylamides and processes for preparing them. Once again, the reaction steps and conditions depicted in Scheme 1 are used.
Substituted 5-hydroxyindolylglyoxylamides and 6-hydroxyindolylglyoxylamides and processes for preparing them and the use thereof as PDE4 inhibitors were described for the first time in DE patent application 198 18 964 A1.
7-Azaindol-3-ylglyoxylamides are disclosed as PDE4 inhibitors in DE patent application 100 53 275 A1, which also describes their preparation and use as therapeutic agents.
4- and 7-Hydroxyindole derivatives, their preparation and use as PDE4 inhibitors are proposed in DE patent application 102 53 426.8.
The invention relates to substituted 7-azaindoles of the general formula 1
and the physiologically tolerated salts thereof.
The compounds of the invention preferably include compounds of the formula 1 in which    A is an N-oxide group and B is carbon (i.e. a CH group or a group CR3 as defined below) or nitrogen. These are the compounds of the invention of the formula 1a
in which    R1             (i) is —C1-10-alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NHC6-14-aryl, —N(C6-14-aryl)2, —N(C1-6-alkyl)(C6-14-aryl), —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14-aryl, —S—C1-6-alkyl, —S—C6-14-aryl, —SO3H, —SO2C1-6-alkyl, —SO2C6-14-aryl, —OSO2C1-6-alkyl, —OSO2C6-14-aryl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl, —O(CO)C1-5-alkyl, by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3–14 ring members or/and by mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5–15 ring members and 1–6 heteroatoms, which are preferably N, O and S, where the C6-14-aryl groups and the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —C1-6-alkyl, —OH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, —SO3H, —SO2C1-6-alkyl, —OSO2C1-6-alkyl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl, and where the alkyl groups on the carbocyclic and heterocylic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H or/and —COOH, or        (ii) is —C2-10-alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NHC6-14-aryl, —N(C6-14-aryl)2, —N(C1-6-alkyl)(C6-14-aryl), —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14-aryl, —S—C1-6-alkyl, —S—C6-14-aryl, —SO3H, —SO2C1-6-alkyl, —SO2C6-14-aryl, —OSO2C1-6-alkyl, —OSO2C6-14-aryl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl, by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3–14 ring members or/and by mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5–15 ring members and 1–6 heteroatoms, which are preferably N, O and S,                    where the C6-14-aryl groups and the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —C1-6-alkyl, —OH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, —SO3H, —SO2C1-6-alkyl, —OSO2C1-6-alkyl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl,            and where the alkyl groups on the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H or/and —COOH,                            R2 is hydrogen or —C1-3-alkyl,    R3 and R4 may be identical or different and are hydrogen, —C1-6-alkyl, —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —SO3H, —SO3—C1-6-alkyl, —COOH, —COO—C1-6-alkyl, —O(CO)—C1-5-alkyl, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, -phenyl or -pyridyl, where the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C1-3-alkyl, —OH, —SH, —NH2, —NHC1-3-alkyl, —N(C1-3-alkyl)2, —NO2, —CN, —SO3H, —SO3C1-3-alkyl, —COOH, —COOC1-3-alkyl, —F, —Cl, —Br, —I, —O—C1-3-alkyl, —S—C1-3-alkyl, or/and —O(CO)C1-3-alkyl, and where the alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H, —SO3C1-3-alkyl, —COOH, —COOC1-3-alkyl, —O—C1-3-alkyl, —S—C1-3-alkyl or/and —O(CO)—C1-3-alkyl.
The compounds of the invention additionally preferably include N-oxides of the formula 1 in which    B is an N-oxide group. These are the compounds of the invention of the formula 1b
in which    A is nitrogen,    R1             (i) is —C1-10-alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NHC6-14-aryl, —N(C6-14-aryl)2, —N(C1-6-alkyl)(C6-14-aryl), —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14-aryl, —S—C1-6-alkyl, —S—C6-14-aryl, —SO3H, —SO2C1-6-alkyl, —SO2C6-14-aryl, —OSO2C1-6-alkyl, —OSO2C6-14-aryl, —COOH, —(CO)C15-alkyl, —COO—C1-5-alkyl —O(CO)C1-5-alkyl, by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3–14 ring members or/and by mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5–15 ring members and 1–6 heteroatoms, which are preferably N, O and S, where the C6-14-aryl groups and the carbocyclic and heterocylic substituents in turn may optionally be substituted one or more times by —C1-6-alkyl, —OH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, —SO3H, —SO2C1-6-alkyl, —OSO2C1-6-alkyl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl, and where the alkyl groups on the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H or/and —COOH, or        (ii) is —C2-10-alkenyl, mono- or polyunsaturated, straight-chain or branched-chain,                    optionally mono- or polysubstituted by —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NHC6-14-aryl, —N (C6-14-aryl)2, —N(C1-6-alkyl)(C6-14-aryl), —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14-aryl, —S—C1-6-alkyl, —S—C6-14-aryl, —SO3H, —SO2C1-6-alkyl, —SO2C6-14-aryl, —OSO2C1-6-alkyl, —OSO2C6-14-aryl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl, —O(CO)C1-5-alkyl, by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3–14 ring members or/and by mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5–15 ring members and 1–6 heteroatoms, which are preferably N, O and S, where the C6-14-aryl groups and the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —C1-6-alkyl-OH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, —SO3H, —SO2C1-6-alkyl, —OSO2C1-6-alkyl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl,            and where the alkyl groups on the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H or/and —COOH,                            R2 is hydrogen or —C1-3-alkyl,    R3 and R4 may be identical or different and are hydrogen, —C1-6-alkyl, —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —SO3H, —SO3—C1-6-alkyl, —COOH, —COO—C1-6-alkyl, —O(CO)—C1-5-alkyl, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, -phenyl or -pyridyl, where the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C1-3-alkyl, —OH, —SH, —NH2, —NHC1-3-alkyl, —N(C1-3-alkyl)2, —NO2, —CN, —COOH, —SO3H, —SO3C1-3-alkyl, —COOC1-3-alkyl, —F, —Cl, —Br, —I, —O—C1-3-alkyl, —S—C1-3-alkyl or/and —O(CO)—C1-3-alkyl, and where alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H, —SO3C1-3-alkyl, —COOH, —COOC1-3-alkyl, —O—C1-3-alkyl, —S—C1-3-alkyl or/and —O(CO)—C1-3-alkyl.
The compounds of the invention additionally include N-oxides of the formula 1 in which    A and B are an N-oxide group. These are the compounds of the invention of the formula 1c
in which    R1             (i) is —C1-10-alkyl, straight-chain or branched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NHC6-14-aryl, —N(C6-14-aryl)2, —N(C1-6-alkyl)(C6-14-aryl), —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14-aryl, —S—C1-6-alkyl, —S—C6-14-aryl, —SO3H, —SO2C1-6-alkyl, —SO2C6-14-aryl, —OSO2C1-6-alkyl, —OSO2C6-14-aryl, —COOH, —(CO)C15-alkyl, —COO—C1-5-alkyl, —O(CO)C1-5-alkyl, by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3–14 ring members or/and by mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5–15 ring members and 1–6 heteroatoms, which are preferably N, O and S, where the C6-14-aryl groups and the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —C1-6-alkyl, —OH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, —SO3H, —SO2C1-6-alkyl, —OSO2C1-6-alkyl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl, and where the alkyl groups on the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H or/and —COOH, or        (ii) is —C2-10-alkenyl, mono- or polyunsaturated, straight-chain or branched-chain, optionally mono- or polysubstituted by —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NHC6-14-aryl, —N(C6-14-aryl)2, —N(C1-6-alkyl)(C6-14-aryl), —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —O—C6-14-aryl, —S—C1-6-alkyl, —S—C6-14-aryl, —SO3H, —SO2C1-6-alkyl, —SO2C6-14-aryl, —OSO2C1-6-alkyl, —OSO2C6-14-aryl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl, —O(CO)C1-5-alkyl, by mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles with 3–14 ring members or/and by mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles with 5–15 ring members and 1–6 heteroatoms, which are preferably N, O and S,                    where the C6-14-aryl groups and the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —C1-6-alkyl, —OH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, —SO3H, —SO2C1-6-alkyl, —OSO2C1-6-alkyl, —COOH, —(CO)C1-5-alkyl, —COO—C1-5-alkyl or/and —O(CO)C1-5-alkyl, and where the alkyl groups on the carbocyclic and heterocyclic substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H or/and —COOH,                            R2 is hydrogen or —C1-3-alkyl,    R3 and R4 may be identical or different and are hydrogen, —C1-6-alkyl, —OH, —SH, —NH2, —NHC1-6-alkyl, —N(C1-6-alkyl)2, —NO2, —CN, —SO3H, —SO3—C1-6-alkyl, —COOH, —COO—C1-6-alkyl, —O(CO)—C1-5-alkyl, —F, —Cl, —Br, —I, —O—C1-6-alkyl, —S—C1-6-alkyl, -phenyl or -pyridyl, where the phenyl or pyridyl substituents in turn may optionally be substituted one or more times by —C1-3-alkyl, —OH, —SH, —NH2, —NHC1-3-alkyl, —N(C1-3-alkyl)2, —NO2, —CN, —SO3H, —SO3C1-3-alkyl, —COOH, —COOC1-3-alkyl, —F, —Cl, —Br, —I, —O—C1-3-alkyl, —S—C1-3-alkyl or/and —O(CO)C1-3-alkyl, and where the alkyl substituents in turn may optionally be substituted one or more times by —OH, —SH, —NH2, —F, —Cl, —Br, —I, —SO3H, —SO3C1-3-alkyl, —COOH, —COOC1-3-alkyl, —O—C1-3-alkyl, —S—C1-3-alkyl or/and —O(CO)—C1-3-alkyl.
Preferred compounds of the formula 1 are those in which R1 is an optionally substituted C1-4-alkyl radical, particularly preferably a C1 radical, with a cyclic substituent. The cyclic substituents are preferably C3-8-cycloalkyl groups or C5-10-aryl or heteroaryl radicals, e.g. phenyl or naphthyl radicals, which may have at least one substituent selected from halogen, i.e. —F, —Cl, —Br or —I, —OH, —NO2, —CN, —CH3, —OCH3 and —CF3.
R2 is preferably H or —CH3. At least one of R3 and R4 is preferably halogen, i.e. —F, —Cl, —Br or —I. R3 and R4 are particularly preferably halogen, e.g. —Cl.
The invention further relates to physiologically tolerated salts of the compounds of formula 1.
The physiologically tolerated salts are obtained in a conventional way by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic or organic bases. Examples of suitable inorganic acids are hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, and examples of suitable organic acids are carboxylic or sulfonic acids, such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid. Examples of suitable inorganic bases are sodium hydroxide solution, potassium hydroxide solution, ammonia, and suitable organic bases are amines, but preferably tertiary amines such as trimethylamine, triethylamine, pyridine, N,N-dimethylaniline, quinoline, isoquinoline, α-picoline, β-picoline, γ-picoline, quinaldine or pyrimidine.
Physiologically tolerated salts of the compounds of formula 1 can additionally be obtained by converting derivatives having tertiary amino groups in a manner known per se with quaternizing agents into the corresponding quaternary ammonium salts. Examples of suitable quaternizing agents are alkyl halides such as methyl iodide, ethyl bromide and n-propyl chloride, but also arylalkyl halides such as benzyl chloride or 2-phenylethyl bromide.
The invention further relates to the D form, the L form and D,L mixtures of compounds of the formula 1 which contain an asymmetric carbon atom, and in the case of a plurality of asymmetric carbon atoms, also the diastereomeric forms. Compounds of the formula 1 which contain asymmetric carbon atoms and usually result as racemates can be separated into the optically active isomers in a manner known per se, for example with an optically active acid. However, it is also possible to employ an optically active starting substance from the outset, in which case a corresponding optically active or diastereomeric compound is obtained as final product.
The compounds of the invention have been found to have pharmacologically important properties which can be utilized in therapy. The compounds of formula 1 can be employed alone, in combination with one another or in combination with other active ingredients.
The compounds of the invention are inhibitors of phosphodiesterase 4. It is therefore an aspect of this invention that the compounds of formula 1 and the salts thereof, and pharmaceutical preparations which comprise these compounds or salts thereof, can be used for the treatment of disorders in which inhibition of phosphodiesterase 4 is beneficial.
These disorders include, for example, inflammations of joints, including arthritis and rheumatoid arthritis, and other arthritic disorders such as rheumatoid spondylitis and osteoarthritis. Further possible uses are the treatment of patients suffering from osteoporosis, sepsis, septic shock, Gram-negative sepsis, toxic shock syndrome, respiratory distress syndrome, asthma or other chronic pulmonary disorders, bone resorption disorders or transplant rejection reactions or other autoimmune diseases such as lupus erythematosus, multiple sclerosis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and chronic demyelinization.
The compounds of the invention can additionally be employed for the therapy of infections such as viral infections and parasitic infections, for example for the therapy of malaria, leishmaniasis, infection-related fever, infection-related muscle pain, AIDS and cachexia, and of non-allergic rhinitis.
The compounds of the invention can likewise be used for the therapy of hyperproliferative disorders, in particular of cancers, for example for the therapy of melanomas, of breast cancer, lung cancer, bowel cancer, skin cancer and of leukemias.
The compounds of the invention can also be employed as bronchodilators and for the treatment of asthma, e.g. for asthma prophylaxis.
The compounds of formula 1 are in addition inhibitors of the accumulation of eosinophils and the activity thereof. Accordingly, the compounds of the invention can also be employed for disorders in which eosinophils are involved. These disorders include, for example, inflammatory respiratory tract disorders such as bronchial asthma, allergic rhinitis, allergic conjuctivitis, atopic dermatitis, eczemas, allergic angiitis, eosinophil-mediated inflammations such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome (pulmonary infiltration with eosinophilia), urticaria, ulcerative colitis, Crohn's disease and proliferative skin disorders such as psoriasis or keratosis.
It is an aspect of this invention that the compounds of formula 1 and salts thereof are also able to inhibit LPS-induced pulmonary neutrophilic infiltration in rats in vivo. The pharmacologically significant properties which have been found prove that the compounds of formula 1 and salts thereof, and pharmaceutical preparations which comprise these compounds or salts thereof, can be utilized therapeutically for the treatment of chronic obstructive pulmonary diseases.
The compounds of the invention additionally have neuroprotective properties and can be used for the therapy of diseases in which neuroprotection is beneficial. Examples of such disorders are senile dementia (Alzheimer's disease), memory loss, Parkinson's disease, depression, strokes and intermittent claudication.
Further possible uses of the compounds of the invention are the prophylaxis and therapy of prostate disorders such as, for example, benign prostate hyperplasia, polyuria, nocturia, and the treatment of incontinence, of colic induced by urinary calculi, and of male and female sexual dysfunctions.
Finally, the compounds of the invention can likewise be used to inhibit the development of drug dependence on repeated use of analgesics such as, for example, morphine, and to reduce the development of tolerance on repeated use of these analgesics.
The drug products are produced by using an effective dose of the compounds of the invention or salts thereof, in addition to conventional adjuvants, carriers and additives. The dosage of the active ingredients may vary depending on the route of administration, age and weight of the patient, nature and severity of the disorders to be treated and similar factors. The daily dose may be given as a single dose to be administered once a day, or divided into 2 or more daily doses, and is usually 0.001–100 mg. Daily dosages of 0.1–50 mg are particularly preferably administered.
Oral, parenteral, intravenous, transdermal, topical, inhalational and intranasal preparations are suitable as administration form. Topical, inhalational and intranasal preparations of the compounds of the invention are particularly preferably used. Galenical pharmaceutical presentations such as tablets, coated tablets, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrup, solutions or drops are used.
Solid drug forms may comprise inert ingredients and carriers such as, for example, calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium stearate or aluminum stearate, methylcellulose, talc, colloidal silicas, silicone oil, high molecular weight fatty acids (such as stearic acid), agar-agar or vegetable or animal fats and oils, solid high molecular weight polymers (such as polyethylene glycol); preparations suitable for oral administration may, if desired, comprise additional flavorings and/or sweeteners.
Liquid drug forms can be sterilized and/or where appropriate comprise excipients such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols to control the osmotic pressure or for buffering and/or viscosity regulators.
Examples of such additions are tartrate buffer and citrate buffer, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). Suitable for controling the viscosity are high molecular weight polymers such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin. Examples of solid carriers are starch, lactose, mannitol, methylcellulose, talc, colloidal silicas, higher molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers such as polyethylene glycol.
Oily suspensions for parenteral or topical uses may be vegetable synthetic or semisynthetic oils such as, for example, liquid fatty acid esters with in each case 8 to 22 C atoms in the fatty acid chains, for example palmitic, lauric, tridecylic, margaric, stearic, arachic, myristic, behenic, pentadecylic, linoleic, elaidic, brasidic, erucic or oleic acid, which are esterified with monohydric to trihydric alcohols having 1 to 6 C atoms, such as, for example, methanol, ethanol, propanol, butanol, pentanol or isomers thereof, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters such as artificial duck preen gland fat, coco fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters inter alia. Likewise suitable are silicone oils differing in viscosity or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, fatty acids such as, for example, oleic acid. It is additionally possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil.
Suitable solvents, gel formers and solubilizers are water or water-miscible solvents. Suitable examples are alcohols such as, for example, ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl Cellosolve, Cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone etc.
Film formers which can be used are cellulose ethers able to dissolve or swell both in water and in organic solvents, such as, for example, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or soluble starches.
Combined forms of gel formers and film formers are likewise perfectly possible. Ionic macromolecules are used in particular for this purpose, such as, for example, sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and salts thereof, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.
Further formulation aids which can be employed are: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin, novantisolic acid.
It may also be necessary to use surfactants, emulsifiers or wetting agents for the formulation, such as, for example, Na lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glyceryl monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride or mono/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts.
Stabilizers such as montmorillonites or colloidal silicas to stabilize emulsions or to prevent degradation of the active substances, such as antioxidants, for example tocopherols or butylated hydroxyanisole, or preservatives such as p-hydroxybenzoic esters, may likewise be necessary where appropriate to prepare the desired formulations.
Preparations for parenteral administration may be present in separate dose unit forms such as, for example, ampoules or vials. Solutions of the active ingredient are preferably used, preferably aqueous solutions and especially isotonic solutions, but also suspensions. These injection forms can be made available as finished product or be prepared only immediately before use by mixing the active compound, e.g. the lyophilisate, where appropriate with further solid carriers, with the desired solvent or suspending agent.
Intranasal preparations may be in the form of aqueous or oily solutions or of aqueous or oily suspensions. They may also be in the form of lyophilisates which are prepared before use with the suitable solvent or suspending agent.
The manufacture, bottling and closure of the products takes place under the usual antimicrobial and aseptic conditions.
The invention further relates to processes for preparing the compounds of the invention.
The compounds of the general formula 1 with the meanings of A, B, R1, R2, R3 and R4 described above are prepared according to the invention
by oxidizing compounds of the formula 1 with the meaning of R1, R2, R3 and R4 described above, in which A is nitrogen and B may be nitrogen or carbon, in a manner known per se by treatment with an oxidizing agent, e.g. an organic peracid, preferably with m-chloroperbenzoic acid or/and peracetic acid, to the compounds of the invention of the formula 1a, 1b or 1c. Mixtures of N-oxides which result where appropriate can be separated in a manner known per se by crystallization or chromatographic methods into the pure compounds of the formula 1a, 1b or 1c.